L2 Diabetes Therapeutics

DM def

• most likely affected organs

• a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

• eyes, kidneys, nerves, heart, and blood vessels

Problems of Diabetes (READ)

• subject to numerous complications, both acute and chronic

• Left uncontrolled, diabetes can affect every organ in the body

• Leading cause of blindness and end-stage renal disease in the U.S. and the 7^th leading cause of death (2023)

• High cost

Metabolic alterations seen in Diabetes Mellitus

• relative or absolute lack of insulin → leads to abnormal metabolism of glucose, protein, and lipids

• end result is prolonged, uncontrolled hyperglycemia

Metabolic syndrome def

grouping of risk factors that inc the risk of heart disease, stroke, and type 2 diabetes

metabolic syndrom diagnose

if 3 or more of following (or taking med for any of the condition

• -        Waist circumference of > 40 inches (men) or 35 inches (women)

  -        Triglycerides ≥ 150 mg/dL; HDL < 40 mg/dL (men) or 50 mg/dL (women)

  -        Fasting glucose ≥ 100 mg/dL

  -        HTN: SBP ≥ 130 mm Hg or DBP ≥ 85 mm Hg

Type 1 vs Type 2

diabetes caused by another disease, hormone problem, medication, or genetic condition, rather than classic T1DM/T2DM.

Pancreas problem → ↓ insulin
Hormone/drug problem → ↑ glucose/insulin resistance
Genetic syndrome → diabetes risk

• Pancreatic disease: Pancreas is damaged → ↓ insulin production

  • Pancreatectomy → pancreas removed

  • Cystic fibrosis → damages pancreas

  • Chronic pancreatitis → pancreatic β-cells damaged/"burned out"

• Endocrinopathies: Excess hormones increase blood glucose → diabetes

  • Acromegaly: ↑ GH → insulin resistance

  • Pheochromocytoma: ↑ catecholamines → ↑ glucose

  • Cushing syndrome: ↑ cortisol → ↑ glucose/insulin resistance

• Drugs/chemicals: Medication causes ↑ glucose or insulin resistance

  • Thiazides

  • Glucocorticoids

  • Atypical antipsychotics

• Genetic syndromes: Genetic disorders can increase risk of diabetes

  • Muscular dystrophies

  • Huntington disease

GDM definition

glucose intolerance first recognized during pregnancy

GDM management

Lifestyle and behavioral management:

• medical nutrition therapy, weight management, glucose monitoring

• physical activity,

Pharmacologic therapy:

• insulin is first-line;

GDM monitoring post partum

• Test women with GDM for prediabetes or diabetes at 4-12 weeks using the 75-g oral glucose tolerance test and clinically appropriate diagnostic criteria

• Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years

who should be tested for diabetes

in overweight or obese (BMI ≥ 25 kg/m² or ≥ 23 kg/m² in individuals of Asian ancestry) adults who have one or more of the following risk factors:

•       First-degree relative with diabetes

•  increasing age (>35)

•       High-risk race, ethnicity, and ancestry (e.g., African American, Latino, Native American, Asian American)

•       History of CVD

•       HTN (≥ 130/80 mmHg or on therapy for hypertension)

•       HDL <35 mg/dL and/or a TG >250 mg/dL

•    ppl w/ polycystic ovary syndrome

•       Physical inactivity

•       Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans, metabolic dysfunction-associated steatotic liver disease (aka MASH/NASH))

HTN levels for considering testing diabetes

≥130/80

lipid levels for considering testing diabetes

HDL <35 mg/dL and/or TG level >250

diabete monitoring testing

• prediabetes

• all other patients, when shoudl testing start

• if results are normal, testing frequency

• annually

• 35 years

• repleated at a minimum of 3 year terva, w/ considering of more frequent testing depending on inital results and risk status

Defining diabetes, prediabetes, normal

• A1C test

• Fasting blood sugar test (no caloric intake for at least 8 hours)

• glucose tolerance test (it’s impaired glucose tolerance when it’s abnormal, include prediabetes and diabetes)

Diabetes only - random plasma glucose diagnostic value

• A1C

  • 5.7 and 6.5

• Fasting blood sugar test

  • 99 and 126

• GTT

  • 140 and 200

Prediabetes Defined by

• A1C 5.7 – 6.4%

• Fasting glucose 100 – 125 mg/dL (Impaired Fasting Glucose – IFG)

• 2-hour plasma glucose 140 – 199 mg/dL during 75 g oral glucose tolerance test (Impaired Glucose Tolerance – IGT)

Patients fitting any of the above should be referred to an intensive lifestyle behavior change program to achieve and maintain a weight reduction of at least 7% of initial body weight through healthy reduced-calorie diet and ≥ 150 min/week of moderate activity physical activity

Criteria for the diagnosis of diabetes

• A1C ≥ 6.5%

• Fasting plasma glucose ≥ 126mg/dL (no caloric intake for at least 8 hours)

• In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (random is any time of the day without regard to time since previous meal)

• 2-hr plasma glucose ≥ 200 mg/dL during oral glucose tolerance test

Diabetes test results requirement in the absence of unequivocal/definite hyperglycemia

• 2 abnormal test results from DIFF test obtained at same time (ex. A1C and FPG) OR

• same test at 2 different times

DCCT trial

T1DM

• Compared intensive vs standard glycemic control in relatively recently diagnosed T1DM.

• Intensive control significantly ↓ microvascular complications (retinopathy, nephropathy) and neuropathy.

EDIC trial

Type 1 DM

• Long-term follow-up of DCCT patients.

• Prior intensive control ↓ any CV event by 42% and ↓ MI, stroke, or CV death by 57%.

• Benefits were strongly associated with the lower A1C achieved during DCCT.

UKPDS trial

Type 2 DM - to see if DCCT applies to type 2

• Compared intensive vs standard control in newly diagnosed T2DM.

• Intensive control ↓ microvascular and neuropathic complications.

• Long-term follow-up showed a “legacy effect”: benefits of early control persisted even later.

• Also showed long-term ↓ MI and all-cause mortality.

ACCORD study

• Compared very intensive control (A1C <6%) vs standard control (A1C 7–7.9%) in patients with CVD or high CVD risk.

• Intensive arm had increased mortality and CV deaths, causing the trial to be stopped early.

  • thought to be tied with hypoglycemia

ADVANCE study

• Compared intensive control with a sulfonylurea +other drugs if needed(A1C ≤6.5% - more moderate) vs standard therapy with any drug except a sulfonylurea with the glycemic target according to “local guidelines”

  • pt were high CVD risk like in ACCORD but had a duration of diabetes htat was 2 year shorter and a lower baseline A1C

• Intensive control ↓ microvascular complications.

• However, there was no reduction in overall mortality or CV mortality.

goals for T2DM

• glycemic control

  • A1C

  • Preprandial plasma glucose

  • peak postprandial plasma glucose

• blood pressure

• lipids

A1C goals differentiation in podraft.

• Note: i think if Q not ask whether fit stringent or less stringent goals, I should just use 7% as typical goal

NO BACK

notes for general insulin idea podraft

Factors affecting insulin absorption

• Concentration → Higher concentration can slow absorption because the injected volume is smaller and more concentrated.

  • ex. Regular U-500 is intermediate acting instead of short acting

• Additives (zinc, protamine) → Slow absorption → prolong insulin action.

• Blood flow to injection site → ↑ blood flow = faster absorption

  • Rubbing/massaging

  • Warm temperature

  • Exercise → ↑ absorption, especially if exercising the injected limb

• Injection site

  • Abdomen → generally fastest and most consistent absorption

Insulin secretion profile in non-diabetic individuals. (JUST READ)

• Between meals/overnight: the pancreas continuously releases a small amount of basal insulin → controls basal glucose, especially glucose released by the liver.

• After a meal: blood glucose rises → pancreas releases a larger bolus/prandial insulin spike → brings glucose back toward baseline.

• This happens at breakfast, lunch, and dinner.

Main takeaway:
Basal insulin = background control all day
Prandial insulin = spikes with meals to cover ↑ glucose

insulin AE

• hypoglycemia

• weight gain

• Injection site reactions: redness, pain, itching, urticaria, edema, and inflammation

• Lipohypertrophy (caused by failing to rotate injection sites with fat accumulation), Lipoatropy (due to insulin antibodies or allergic-type reactions that destroy the fat at the site of injection)

Hypoglycemia symptoms

1. sympathetic and parasympathetic NS🚨
Think “Pale, Sweaty, Shaky, Hungry, Heart racing”

• Pallor

• Sweating

• Trembling

• Hunger

• Tachycardia/palpitations

2. CNS = BRAIN NEEDS GLUCOSE 🧠
Tired → Moody → Confused/abnormal → Can't think/see → Seizure → Coma

• Fatigue, irritability, headache

• ↓ concentration / mental activity; Confusion, abnormal behavior

• Blurred/clouded vision

• Convulsions

• Loss of consciousness → coma → death

Classification of hypoglycemia

• level 1

• level 2

• level3

level 1 < 70 mg/dL  and ≥ 54 mg/dL

level 2 <54 mg/dL

level 3 see pic

Metformin GI AE

• GI — n/v/d flatulence, dyspepsia, abdominal pain

  • titrate slowly

• lactic acidosis (don’t use w/ lactic acidosis risk factor — see another card)

• B12 deficiency — may result in anemia and neuropathy

Lactic acidosis risk factors for metformin

• hepatic or kidney impairment, surgery and other procedure due to potential for volume depletion, hypotension and kidney impairment

• radiologic study with contrast — contrast can cause nephropathy

• reduced tissue perfusion (HF, sepsis); hypoxic states (acute HF, acute MI< sepsis, shock)

• excessive alcohol intake

GLP-1 agonist AE

GI related

• GLP slow down food going through body, so AE related to GI. Abdominal pain, constipation, diarrhea, nausea, vomiting, decreased appetite, dyspepsia (another stomach pain)

• Gallbladder disease: choleithiasis (gall stone), cholecystitis (gallbladder inflammation)

• pancreatitis (including hemorrhagic and necrotizing w/ some fatalities)

- Diabetic retinopathy complication

- CI if personal/family history of medullary thyroid carcinoma and in pt with multiple endocrine neoplasia syndrome type 2 (MEN2)

DDP4 inhibitor AE

• Upper respiratory tract infection

• HF hospitalizations (seen in alogliptin, saxagliptin)

• pancreatitis

• severe joint pain (resolves upon discontinuation

• stuffy or runny nose, headache

SGLT2 AE

• UTI - cuz glucose in urine; Genitourinary mycotic infection (fungal); Fournier gangrene (necrotizing fasciitis of the perineum - the area between the genitals and the anus.)

• polyuria

• ketoacidosis – this is not bc glucose. So this is Euglycemic DKA.

  • add dextrose to fluid upon initiation!

• lower limb amputation (higher incidence if neuropathy), bone fractures (? From falls due to hypotension due to hypovolemia)

thiazolidinedione AE

💧 Think: “TZDs make you PUFFY”

Fluid-related

• dose related Weight gain → fluid retention + fat accumulation

• ↓ Hgb/Hct → dilution from ↑ plasma volume

• Macular Edema – see ophthalmologist if vision symptoms develop during therapy

• Heart failure → dose dependent, reversible w/ discontinuation; fluid retention worsens HF

Other major AEs

• 🫙 Bladder cancer – long-term use, high-dose exposure

• 🦴 Fractures – class-related comment; conflicting evidence with pioglitazone

• 🧪 Hepatic effects – more with older agents but has been reported with pioglitazone

Sulfonylurea AE

• Hypoglycemia – glyburide has highest risk due to active metabolite (esp with renal insufficiency. Bc active metabolite is renally cleared)

• Weight gain

• Sulfa allergy – low rate of cross-reactivity

  • But Most ppl with sulfa antibiotic allergy can take this

Meglitinide AE

• Hypoglycemia (higher incidence with repaglinide)

  • Should skip dose when skip the meal

• Weight gain

a-Glucosidase Inhibitors AE

Think: 💨 GUT + LIVER

• GI: 💨 flatulence (most common), diarrhea, abdominal pain

• Liver: ↑ liver enzymes → monitor LFTs every 3 mo for first year of therapy, then periodically

• Hypoglycemia: ❌ doesn't cause it alone as primary tx

  • Can occur when combined with insulin/sulfonylurea

  • If hypo occurs → treat with GLUCOSE (dextrose), NOT sucrose/complex carbs

Colesevelam AE

o   Constipation

o   Increased triglycerides

Bromocriptine AE

• Dizziness, syncope, nausea

• Fatigue

• Rhinitis

DKA and HHS basic mechanism

a reduction in the net effective action of circulating insulin coupled with a concomitant elevation of counterregulatory hormones, such as glucagon, catecholamines, cortisol, and growth hormone

•       Increased hepatic glucose production (glycogenolysis, gluconeogenesis)

•       Impaired glucose utilization in peripheral tissues

•       Hyperglycemia

DKA

o   the combination of insulin deficiency and increased counterregulatory hormones leads to release of FFA into the circulation from adipose tissue (lipolysis) and unrestrained hepatic fatty acid oxidation to ketone bodies

•       Ketonemia

•       Metabolic acidosis

HHS

Compared w/ DKA, there’s less severe insulin deficiency → sufficient insulin to prevent ketogenesis but not enough to prevent hyperglycemia, due to inc hepatic glucose production and dec glucose utilization by peripheral tissues

• note: patient usually don’t notice it until HHS.

Precipitating factors for absolute insulin deficiency

•       Newly diagnosed type 1 diabetic

•       Omission of insulin therapy

precipitating factors for relative insulin deficiency (more type 2) resulting from excess counter-regulatory hormone secretion (glucagon, catecholamine, cortisol, growth hormone, thyroid hormone

•       Infection, Pancreatitis

•       Cerebrovascular accident, Trauma, MI

•       Alcohol abuse

•       Drugs

Diagnostic characteristic for DKA

DKA

• Diabetes/hyperglycemia: glucose ≥200 mg/dL OR prior history of diabetes

• Ketosis: Beta-hydroxybutyrate concentration ≥3 mmol/L or Urine ketone strip 2+ or greater

• Acidosis (metabolic): pH < 7.3 and/or [Bicarb] < 18 mmol/L

HHS diagnostic criteria

• hyperglycemia: plasma glucose ≥600 mg/dL

• Hyperosmolarity:

  • effective serum osmolality >300 mOsm/kg (2Na + glucose)

  • OR total serum osmolarity > 320 mOsm/kg (2Na + glucose + urea)

• abSence of significant ketonemia: beta hydroxybutyrate < 3 or Urine ketone strip < 2+

• absence of acidosis: pH ≥7.3 and Bicarb ≥15

DKA classification

• mild

• moderate

• severe

glucose is all ≥200

K: 3-6 for mild and moderate. severe is >6

A: 7.3, 7.25, 7

Symptoms and signs of DKA and HHS